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E3 ubiquitin ligase RNF126 (ring finger protein 126) is highly expressed in various cancers and strongly associated with tumorigenesis. However, its specific function in bladder cancer (BCa) is still debatable. Here, we found that RNF126 was significantly upregulated in BCa tissue by TCGA database, and our studies indicated that downregulation of RNF126 significantly inhibited cell proliferation and metastasis through the EGFR/PI3K/AKT signaling pathway in BCa cells. Furthermore, we identified PTEN, an inhibitor of the PI3K/AKT signaling pathway, as a novel substrate for RNF126. By co-immunoprecipitation assays, we proved that RNF126 directly interacts with PTEN. Predominantly, PTEN binds to the C-terminal containing the RING domain of RNF126. The in vivo ubiquitination assay showed that RNF126 specifically regulates PTEN stability through poly-ubiquitination. Furthermore, PTEN knockdown restored cell proliferation, metastasis, and tumor formation of BCa cells inhibited by RNF126 silencing in vitro and in vivo. In conclusion, these results identified RNF126 as an oncogene that functions through ubiquitination and degradation of PTEN in BCa.

Chemoresistance to cisplatin is a principal cause of treatment failure and mortality of advanced bladder cancer (BC). The underlying mechanisms remain unclear, which hinders the development of preventive strategies. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC. This study explores the role of PKM2 in chemoresistance and whether inhibiting PKM2 augments the chemosensitivity to cisplatin and reduces BC growth and progression. We found that Shikonin binds PKM2 and inhibits BC cell survival in a dose-dependent but pyruvate kinase activity-independent manner. Down-regulation of PKM2 by shRNA blunts cellular responses to shikonin but enhances the responses to cisplatin. Shikonin and cisplatin together exhibit significantly greater inhibition of proliferation and apoptosis than when used alone. Induced cisplatin-resistance is strongly associated with PKM2 overexpression, and cisplatin-resistant cells respond sensitively to shikonin. In syngeneic mice, shikonin and cisplatin together, but not as single-agents, markedly reduces BC growth and metastasis. Based on these data, we conclude that PKM2 overexpression is a key mechanism of chemoresistance of advanced BC to cisplatin. Inhibition of PKM2 via RNAi or chemical inhibitors may be a highly effective approach to overcome chemoresistance and improve the outcome of advanced BC.

Background Bladder cancer, a widely occurring malignant tumor worldwide, is closely related to the abnormal activation of numerous signaling pathways during its initiation, progression, and metastasis. Protein kinase D2 (PRKD2), as a member of the protein kinase D family, exerts a pivotal influence on human cancers. This research aimed to elucidate the involvement and mechanism of PRKD2 in bladder cancer. Methods PRKD2 expression was analyzed using quantitative real-time PCR, Western blotting and tissue microarray (n = 30). Functional experiments were conducted to evaluate the biological phenotypes of cells, including CCK-8 assay, colony formation assay, flow cytometry analysis, scratch wound healing assay, Transwell migration assay, and mouse xenograft model. The phosphorylation of MCM2 by PRKD2 was examined using site-directed mutagenesis and immunoprecipitation assay assays. Results Our results revealed markedly elevated expression levels of PRKD2 in bladder cancer compared to control tissues. Increased PRKD2 expression was associated with lymph node metastasis, distant metastasis, advanced TNM staging, and poorer prognosis. Functional experiments demonstrated that depletion of PRKD2 impeded the proliferation, migration, invasion, and epithelial-mesenchymal transition of bladder cancer cells in vitro and in vivo. Mechanistically, PRKD2 phosphorylates complex component 2 (MCM2) at serine 139. This phosphorylation drives the malignant progression of bladder cancer cells. Conclusions These findings offer new insights into regulatory mechanisms involving PRKD2 contributing to the malignancy of bladder cancer, thereby presenting a potential therapeutic target.

High aerobic glycolysis not only provides energy to cancer cells, but also supports their anabolic growth. JMJD1A, a histone demethylase that specifically demethylates H3K9me1/2, is overexpressed in multiple cancers, including urinary bladder cancer (UBC). It is unclear whether JMJD1A could promote cancer cell growth through enhancing glycolysis. In this study, we found that downregulation of JMJD1A decreased UBC cell proliferation, colony formation and xenograft tumor growth. Knockdown of JMJD1A inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including GLUT1, HK2, PGK1, PGM, LDHA and MCT4 . Mechanistically, JMJD1A cooperated with hypoxia inducible factor 1α (HIF1α), an important transcription factor for glucose metabolism, to induce the glycolytic gene expression. JMJD1A was recruited to the promoter of glycolytic gene PGK1 to demethylate H3K9me2. However, the JMJD1A (H1120Y) mutant, which loses the demethylase activity, failed to cooperate with HIF1α to induce the glycolytic gene expression, and failed to demethylate H3K9me2 on PGK1 promoter, suggesting that the demethylase activity of JMJD1A is essential for its coactivation function for HIF1α. Inhibition of glycolysis through knocking down HIF1α or PGK1 decelerated JMJD1A-enhanced UBC cell growth. Consistent with these results, a positive correlation between JMJD1A and several key glycolytic genes in human UBC samples was established by analyzing a microarray-based gene expression profile. In conclusion, our study demonstrates that JMJD1A promotes UBC progression by enhancing glycolysis through coactivation of HIF1α, implicating that JMJD1A is a potential molecular target for UBC treatment.

Background Bladder cancer (BC) is the most common cancer of the urinary bladder and upper tract, in which the clinical management is limited. AURKA (aurora kinase A) has been identified as an oncogene in cancer development; however, its potential role and underlying mechanisms in the progression of BC remain unknown. Results In this study, we evaluated Aurora kinase A (AURKA) expression in patient samples by performing gene expression profiling, and found that AURKA expression levels were significantly higher in BC tissues than in normal tissues. Increased AURKA in BC was strongly associated with stage and grade. Moreover, BC patients with elevated AURKA achieved poor overall survival rates. The experiments in vitro comprehensively validated the critical role of AURKA in promoting BC cell proliferation using the methods of gene overexpression and gene silencing. Furthermore, we proved that AURKA inhibitor MLN8237 arrested BC cell growth and induced apoptosis. Conclusions These findings implicate AURKA acting as an effective biomarker for BC detection and prognosis, as well as therapeutic target.

Bladder cancer (BC) is the ninth most malignant tumor worldwide. Some BC patients will develop muscle‐invasive BC (MIBC), which has a 5‐year survival rate of approximately 60% due to metastasis. As such, there is an urgent need for novel therapeutic and diagnostic targets for MIBC. Analysis of novel antitumor microRNA (miRNA)‐mediated cancer networks is an effective strategy for exploring therapeutic targets and prognostic markers in cancers. Our previous miRNA analysis revealed that miR‐140‐5p acts as an antitumor miRNA in BC cells. Here, we investigated miR‐140‐5p regulation of BC molecular pathogenesis. Procollagen‐lysine, 2‐oxoglutarate 5‐dioxygenase 1 (PLOD1) was found to be directly regulated by miR‐140‐5p, and aberrant expression of PLOD1 was observed in BC clinical specimens. High PLOD1 expression was significantly associated with a poor prognosis (disease‐free survival: P = 0.0204; overall survival: P = 0.000174). Multivariate analysis showed PLOD1 expression to be an independent prognostic factor in BC patients (hazard ratio = 1.51, P = 0.0099). Furthermore, downregulation of PLOD1 by siRNAs and a specific inhibitor significantly decreased BC cell aggressiveness. Aberrant expression of PLOD1 was closely associated with BC pathogenesis. In summary, the present study showed that PLOD1 may be a potential prognostic marker and therapeutic target for BC. miR‐140‐5p suppressed tumor cell growth, migration, and invasion activities via targeting of procollagen‐lysine, 2‐oxoglutarate 5‐dioxygenase 1 (PLOD1), which promotes collagen cross‐linking in bladder cancer. PLOD1 was highly expressed in bladder cancer tissues, and inhibition of PLOD1 attenuated cancer cell aggressiveness. High PLOD1 expression was significantly associated with poor clinical outcome. Targeting PLOD1 might be a therapeutic target in bladder cancer.

Background Metastasis remains a predominant contributor to cancer-related mortality worldwide. Elucidating the molecular mechanisms underlying cancer metastasis is crucial for developing strategies to inhibit tumor progression and improve clinical outcomes. Protein glycosylation, a hallmark of cancer pathogenesis mediated by specific glycosyltransferases, has emerged as a critical regulatory mechanism. This study investigates the functional role of glycosylation in cancer progression and explores its therapeutic potential. Methods We employed an integrated approach combining bioinformatics analysis of datasets, in vitro biological assays, transcriptional profiling, immunoprecipitation, and lectin pull-down assays to characterize α1,3-mannosyltransferase (ALG3)-dependent glycosylation mechanism in bladder cancer metastasis. Therapeutic targeting was investigated through virtual screening, molecular docking, molecular dynamics simulation, cellular thermal shift assay (CETSA), and validated in nude mice model using the Tranditional Chinese Medicine (TCM) monomer (NDGA). Results Our analysis revealed significantly elevated ALG3 expression in bladder cancer patients. Combined measurement of ALG3 in urine and serum samples demonstrated strong diagnostic potential, with higher AUC, sensitivity and specificity. Mechanistically, ALG3 promoted oncogenic cell behaviors through Ras signaling pathway activation. Immunoprecipitation and lectin pull-down assays identified LRFN4 as a novel ALG3 target, with ALG3 mediated N-glycosylation of LRFN4 being essential for its oncogenic function. Virtual screening identified nordihydroguaiaretic acid (NDGA) as a potent ALG3 inhibitor, which was validated through molecular docking, molecular dynamics simulation and CETSA. NDGA exhibited significant anti-tumor effects in both in vitro and in vivo models. Conclusions Our findings established ALG3 as a promising detection glycobiomarker for bladder cancer, and a key regulator for metastasis through LRFN4 N-glycosylation and Ras signaling pathway activation. The identified ALG3 inhibitor-NDGA demonstrated significant therapeutic potential, offering a foundation for developing personalized treatment strategies against bladder cancer metastasis.

The O‐ glycan branching enzyme, core2 β ‐1,6 ‐ N ‐ acetylglucosaminyltransferase (C2GnT), forms O‐ glycans containing an N‐ acetylglucosamine branch connected to N‐ acetylgalactosamine (core2 O‐ glycans) on cell‐surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT‐expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT‐expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK‐activating receptor, NKG2D, by its tumour‐associated ligand, Major histocompatibility complex class I‐related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT‐expressing bladder tumour cells, poly ‐ N ‐ acetyllactosamine was present on core2 O‐ glycans on MICA, and galectin‐3 bound the NKG2D‐binding site of MICA through this poly ‐ N ‐ acetyllactosamine. Galectin‐3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT‐expressing bladder tumour cells, resulting in tumour metastasis. This paper illuminates a new mechanism for tumour cell evasion from the immune surveillance. Molecular analyses reveal modifications of the NKG2D‐NKG2DL system that prevent natural killer cell activation.

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. “Acetyl-chromatin” homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation.